PRDM10 directs FLCN expression in a novel disorder overlapping with Birt-Hogg-Dubé syndrome and familial lipomatosis

  • Hum Mol Genet. 2023 Mar 20;32(7):1223-1235. doi: 10.1093/hmg/ddac288.
Irma van de Beek  1 ,  Iris E Glykofridis  2 ,  Jan C Oosterwijk  3 ,  Peter C van den Akker  3 ,  Gilles F H Diercks  4 ,  Maria C Bolling  5 ,  Quinten Waisfisz  1 ,  Arjen R Mensenkamp  6 ,  Jesper A Balk  2 ,  Rob Zwart  1 ,  Alex V Postma  1  7 ,  Hanne E J Meijers-Heijboer  2 ,  R Jeroen A van Moorselaar  8 ,  Rob M F Wolthuis  2 ,  Arjan C Houweling  1
Affiliations
  • 1. Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Human Genetics, De Boelelaan 1117, Amsterdam, The Netherlands.
  • 2. Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Human Genetics and Cancer Center Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands.
  • 3. University of Groningen, University Medical Center Groningen, Department of Genetics, Hanzeplein 1, Groningen, The Netherlands.
  • 4. University of Groningen, University Medical Center Groningen, Department of Pathology, Hanzeplein 1, Groningen, The Netherlands.
  • 5. University of Groningen, University Medical Center Groningen, Department of Dermatology, Hanzeplein 1, Groningen, The Netherlands.
  • 6. Radboudumc, Department of Human Genetics, Geert Grooteplein Zuid 10, Nijmegen, The Netherlands.
  • 7. Department of Medical Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
  • 8. Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Urology and Cancer Center Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands.
PMID: 36440963 DOI: 10.1093/hmg/ddac288
Abstract

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder characterized by fibrofolliculomas, pulmonary cysts, pneumothoraces and renal cell carcinomas. Here, we reveal a novel hereditary disorder in a family with skin and mucosal lesions, extensive lipomatosis and renal cell carcinomas. The proband was initially diagnosed with BHD based on the presence of fibrofolliculomas, but no pathogenic germline variant was detected in FLCN, the gene associated with BHD. By whole exome Sequencing we identified a heterozygous missense variant (p.(Cys677Tyr)) in a zinc-finger encoding domain of the PRDM10 gene which co-segregated with the phenotype in the family. We show that PRDM10Cys677Tyr loses affinity for a regulatory binding motif in the FLCN promoter, abrogating cellular FLCN mRNA and protein levels. Overexpressing inducible PRDM10Cys677Tyr in renal epithelial cells altered the transcription of multiple genes, showing overlap but also differences with the effects of knocking out FLCN. We propose that PRDM10 controls an extensive gene program and acts as a critical regulator of FLCN gene transcription in human cells. The germline variant PRDM10Cys677Tyr curtails cellular folliculin expression and underlies a distinguishable syndrome characterized by extensive lipomatosis, fibrofolliculomas and renal cell carcinomas.